EP3808270A1 - Appareil, système et procédé de surveillance d'écoulement de sueur - Google Patents

Appareil, système et procédé de surveillance d'écoulement de sueur Download PDF

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Publication number
EP3808270A1
EP3808270A1 EP19202953.6A EP19202953A EP3808270A1 EP 3808270 A1 EP3808270 A1 EP 3808270A1 EP 19202953 A EP19202953 A EP 19202953A EP 3808270 A1 EP3808270 A1 EP 3808270A1
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EP
European Patent Office
Prior art keywords
sweat
sensor
droplet
droplets
chamber
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP19202953.6A
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German (de)
English (en)
Inventor
Eduard Gerard Marie Pelssers
Kiran Hamilton J. DELLIMORE
Ron Martinus Laurentius Van Lieshout
Lutz Christian GERHARDT
Peter Hermanus Bouma
Mark Thomas Johnson
Laurentia Johanna Huijbregts
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Koninklijke Philips NV
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Koninklijke Philips NV
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Publication date
Application filed by Koninklijke Philips NV filed Critical Koninklijke Philips NV
Priority to EP19202953.6A priority Critical patent/EP3808270A1/fr
Priority to JP2022522387A priority patent/JP7209129B2/ja
Priority to CN202080072261.8A priority patent/CN114585306A/zh
Priority to US17/769,024 priority patent/US20240099647A1/en
Priority to EP20786576.7A priority patent/EP4044922B1/fr
Priority to PCT/EP2020/078304 priority patent/WO2021074010A1/fr
Publication of EP3808270A1 publication Critical patent/EP3808270A1/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14507—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood
    • A61B5/14517—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for sweat
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/42—Detecting, measuring or recording for evaluating the gastrointestinal, the endocrine or the exocrine systems
    • A61B5/4261—Evaluating exocrine secretion production
    • A61B5/4266—Evaluating exocrine secretion production sweat secretion
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502769—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements
    • B01L3/502784—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements specially adapted for droplet or plug flow, e.g. digital microfluidics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1468—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means
    • A61B5/1477—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means non-invasive
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6801—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
    • A61B5/683—Means for maintaining contact with the body
    • A61B5/6832—Means for maintaining contact with the body using adhesives
    • A61B5/6833—Adhesive patches
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0694—Creating chemical gradients in a fluid
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0663—Whole sensors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0848—Specific forms of parts of containers
    • B01L2300/0851—Bottom walls
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0864—Configuration of multiple channels and/or chambers in a single devices comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0867—Multiple inlets and one sample wells, e.g. mixing, dilution
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/16—Surface properties and coatings
    • B01L2300/161—Control and use of surface tension forces, e.g. hydrophobic, hydrophilic
    • B01L2300/165—Specific details about hydrophobic, oleophobic surfaces
    • B01L2300/166—Suprahydrophobic; Ultraphobic; Lotus-effect

Definitions

  • the other electrode is mounted in the chamber.
  • the electrodes are thus shorted by the connection provided by the sweat in the chamber and the sweat droplet which is still attached thereto. This shorting of the electrodes immediately prior to release of the sweat droplet into the wick enables the device to count the sweat droplets.
  • the design nevertheless necessitates provision of a sweat rate sensor per chamber. This makes the arrangement disadvantageously complex. Moreover, the design may be incompatible with the provision of alternative sweat droplet sensing principles.
  • the apparatus releases the sweat droplets from the outlet before transporting the sweat droplets to the sensor, there is no requirement for a sensor to be provided for each chamber, e.g. in order to sense the sweat droplet while it is still attached to the bulk of the sweat collected in the chamber, as in the prior art devices.
  • the present apparatus may correspondingly provide greater design flexibility.
  • the apparatus may transport sweat to a sensor which is spatially removed from the outlet, and any suitable sweat sensing device may be contemplated for sensing the sweat droplets supplied thereto by the apparatus.
  • the fluid transport assembly may comprise a surface for transporting the sweat droplets thereon.
  • the surface may, for example, be provided with alternating hydrophobic and hydrophilic domains for transporting the sweat droplets.
  • the domains are arranged to have a gradual change in distribution over the length of the surface in the direction of the sensor. This may be regarded as providing the surface with a "chemical gradient" for releasing the sweat droplet from the outlet and/or transporting the sweat droplet towards the sensor.
  • the surface may be inclined and arranged such that, when the apparatus is orientated for use, the sweat droplet is released from the outlet and/or transported towards the sensor at least partly by gravity acting to pull the sweat droplet down the inclined surface.
  • This topological gradient may facilitate release of the sweat droplet from the outlet and/or transport of the sweat droplet towards the sensor.
  • the chemical and topological gradients may be regarded as "passive" gradients, since these gradients do not require the fluid transport assembly to actively apply a force in order to overcome the contact angle hysteresis of the sweat droplet, i.e. the forces resisting movement of the sweat droplet.
  • the fluid transport assembly may be configured to provide a flow of carrier fluid for releasing the sweat droplet and/or transporting the sweat droplet to the sensor.
  • the surface is a contoured surface with the outlet being provided at a summit of the contoured surface
  • the fluid transport assembly may be arranged to direct the flow of carrier fluid at the sweat droplet protruding from the outlet at the summit. This structure may facilitate detachment of the sweat droplet, since less energy is required to overcome the droplet inertia caused by contact angle hysteresis.
  • the electrowetting arrangement and the pressure gradient may be regarded as providing "active" sweat droplet release and/or transportation methods, since the fluid transport assembly actively exerts force in order to overcome the contact angle hysteresis of the sweat droplet.
  • the fluid transport assembly may comprise a further surface which opposes the outlet, the further surface being spaced from the outlet such that the protruding sweat droplet is released therefrom upon contacting the further surface.
  • the further surface may thus lead to the formation of sweat droplets of a relatively uniform size/volume, since the size of each sweat droplet is determined by the separation between the outlet and the further surface.
  • the sweat droplets formed on the further surface may be transported via the further surface to the sensor.
  • the electrowetting arrangement described above may be used for this purpose, by the series of electrowetting tiles being arranged on the further surface.
  • the frequency of the electrowetting waves provided by the electric field generator may be higher than the frequency at which the sweat droplets are released onto the further surface. In this manner, uniformly sized sweat droplets may be transported to the sensor with well-defined separation between consecutive sweat droplets.
  • the fluid transport assembly may be configured to control the separation between the further surface and the outlet based on the measure of the sweat rate, e.g. provided by the sensor.
  • the measure of the sweat rate e.g. provided by the sensor.
  • fast and uncontrolled sweat droplet formation may be mitigated by increasing the separation, since it may take a longer time to detach a larger sweat droplet onto the further surface.
  • decreasing the separation may serve to increase the number of (smaller) sweat droplets formed on the further surface.
  • the electric field generator may be configured to adjust the frequency of the electrowetting waves in response to a measure of the sweat rate.
  • the plurality of chambers may be arranged in groups, a subset of the plurality of chambers belonging to each group, wherein the fluid transport assembly comprises: a first interconnection per group; first branches for fluidly connecting each chamber of the respective group to the first interconnection; a second interconnection per two or more groups; and second branches for fluidly connecting the first interconnections to one respective second interconnection, wherein each of the second interconnections is fluidly connectable to the sensor.
  • the fluid transport assembly may, for example, further comprise: a third interconnection per two or more of the second interconnections; and third branches for fluidly connecting the two or more second interconnections to one respective third interconnection, wherein the third interconnection is fluidly connectable to the sensor.
  • This branched structure may enable efficient transportation of numerous sweat droplets, collected from various skin locations, towards the sensor.
  • the sensor may comprise a channel which is dimensioned such that each of the sweat droplets forms a meniscus at the head and tail of the sweat droplet spanning the cross-section of the channel.
  • the sweat droplet may correspondingly adopt the shape of the channel. This may assist the sensor to determine variation in volume of the sweat droplets, e.g. in comparison to the scenario in which sweat droplets passing through the sensor retain their original hemispherical shape.
  • a method for transporting sweat droplets to a sensor comprising: filling a chamber with sweat received from the skin, until a sweat droplet protrudes from an outlet of the chamber; releasing the protruding sweat droplet from the outlet; and transporting the released sweat droplet to the sensor, the outlet being thereby made available for a subsequent sweat droplet to form and protrude therefrom upon further filling of the chamber, wherein the released sweat droplet is transported at least as fast as the subsequent sweat droplet protrudes from the outlet such that the respective sweat droplets do not contact each other, i.e. do not contact each other upstream of the sensor.
  • Evaporation becomes a disturbing factor leading to artificially elevated biomarker concentrations. Evaporation can also inhibit or prevent sweat from reaching the sensor, especially at low sweat rates (in the order of 0.2 nl/min/gland) and volumes.
  • a further disadvantage of conventional sweat sensing devices is that the electrochemical sensors, often used for semi-continuous measurement, may require frequent recalibration and offline calibration. This may have a negative workflow impact when such devices are used for monitoring a subject.
  • the apparatus comprises a chamber for filling with sweat.
  • the chamber has an inlet lying adjacent the surface of the skin, which inlet permits sweat to enter and fill the chamber.
  • the chamber has an outlet from which a sweat droplet protrudes once the chamber has been filled.
  • the apparatus further comprises a fluid transport assembly which is designed to enable the sweat droplet protruding from the outlet to become detached from the outlet of the chamber.
  • the sweat droplet is subsequently transported by the fluid transport assembly to the sensor. Once the protruding droplet has been released from the outlet, the outlet is made available for a subsequent sweat droplet to protrude therefrom upon further filling of the chamber.
  • the released sweat droplet is transported via the fluid transport assembly at least as fast as the subsequent sweat droplet protrudes from the outlet such that the respective sweat droplets do not contact each other before reaching the sensor.
  • the apparatus supplies sweat to the sensor in a dropwise manner.
  • the apparatus provides the sensor with a discretised flow of sweat instead of the continuous flow of sweat used in conventional sweat sensing devices.
  • the fluid transport assembly causes the sweat droplet to be released from the outlet of the chamber and transported to the sensor.
  • the migration of droplets towards, and in some examples through, the sensor may, for instance, be via an interfacial tension method and/or by application of pressure, as will be further described herein below.
  • the dropwise or discretised flow of sweat offers several unique benefits with respect to continuous flow.
  • the delay between excretion of sweat and the actual determination of the biomarker concentration may be reduced, e.g. from typically 1-2 hours to about 10-15 minutes for subjects in a sedentary state.
  • the capability of handling minute amounts of sweat and being able to transport this relatively rapidly to the sensor may enable, in the case of the sensor comprising a biomarker sensor, biomarker concentrations to be determined, even when subjects are in a sedentary state.
  • the sweat rate may be more straightforwardly determined, e.g. using simpler sensors, when the sweat is provided as discrete sweat droplets rather than as a continuous flow.
  • the apparatus releases the sweat droplets from the outlet before transporting the sweat droplets to a sensor, there is no requirement for a sensor to be provided for each chamber, e.g. in order to sense the sweat droplet while it is still attached to the bulk of the sweat collected in the chamber, as in some of the prior art devices.
  • the present apparatus may correspondingly provide greater design flexibility.
  • the apparatus may transport sweat to a sensor which is spatially removed from the outlet.
  • the fluid transport assembly may comprise a surface extending between the outlet and the sensor.
  • the surface may have, for example, a topological and/or chemical gradient down which the sweat droplets migrate to the sensor during use of the apparatus.
  • An electrowetting technique may alternatively or additionally be used. Such an electrowetting technique uses an electric field to effect transient modification of the wetting properties of a surface in order to cause migration of the sweat droplet along the surface towards the sensor.
  • the resulting train of sweat droplets can be detected and counted by using, for instance, a simple detector having a pair of electrodes between which each sweat droplet passes.
  • a facile means of measuring the sweat rate is correspondingly provided.
  • the inlet 104 is shown proximal to a sweat gland 108.
  • the sweat excreted by the sweat gland 108 enters and fills the chamber 102 via the inlet 104.
  • the apparatus 100 may comprise a plate 110 which is attached to the surface of the skin 106.
  • a lower surface of the plate 110 is in direct contact with the surface of the skin 106.
  • the chamber 102 takes the form of an aperture delimited by the plate 110.
  • the plate 110 may be formed of any suitable material, e.g. a polymer, capable of being disposed on the skin.
  • the plate 110 may have at least a degree of flexibility so as to enable conformal application to the surface of the skin 106. More rigid plates 110 may also be contemplated, providing the inlet 104 can receive sweat from the skin 106.
  • the plate 110 may, for instance, be adhered to the surface of the skin 106 using a suitable biocompatible adhesive.
  • the plate 110 may be held against the surface of the skin 106 by fastenings, e.g. straps, for attaching the plate 110 to the body of the subject.
  • the diameter of the inlet 104 for receiving sweat from the skin 106 is selected to be relatively small, for example 200-2000 ⁇ m, such as 300-1200 ⁇ m, e.g. about 360 ⁇ m or about 1130 ⁇ m.
  • the diameter of sweat gland outlets on the surface of the skin 106 are typically in the range of about 60 ⁇ m to 120 ⁇ m.
  • a relatively small inlet 104 may assist to reduce the chances of two or more sweat glands 108 excreting into the same inlet 104, which can complicate interpretation of sensor signals, as will be explored in further detail below.
  • the apparatus 100 may, for instance, include a plurality of such chambers 102, for example 2 to 50 chambers 102, such as 10 to 40 chambers 102, e.g. about 25 chambers 102.
  • a sweat droplet 112 protrudes from an outlet 114 of the chamber 102.
  • the outlet 114 is delimited by an upper surface of the plate 110, and a hemispherical sweat droplet 112 forms on top of the outlet 114 once the chamber 102 has been filled with sweat.
  • the apparatus 100 may be configured such that the speed of formation of the sweat droplet 112 is determined by the sweat rate, while the volume of the sweat droplet 112 is determined by the fluid transport assembly. This will be explained in further detail.
  • the respective areas of the inlet 104 and the outlet 114 may be selected to ensure efficient filling of the chamber 102 and sweat droplet 112 formation over a range of sweat rates.
  • the inlet 104 and the outlet 114 have selected fixed dimensions for this purpose.
  • the apparatus 100 may be configurable such that at least some of the dimensions and geometry relevant to sweat droplet 112 formation can be varied.
  • the chamber 102 is dimensioned to fill up with sweat within 10-15 minutes.
  • the formation of the hemispherical sweat droplet 112 following filling of the chamber 102 preferably occurs typically within 10 seconds at relatively low sweat rate, e.g. 0.2 nl/min/gland.
  • the apparatus 100 may enable the formation of relatively uniformly sized sweat droplets 112, and in addition may handle variable sweat droplet 112 volumes as well.
  • the sensor to which the apparatus 100 transports the sweat droplets 112 may be configured to both count the sweat droplets 112 and determine the time it takes for each sweat droplet 112 to pass through the sensor. This time is linearly related via the a priori known migration speed to the volume of the sweat droplet 112, as will be explained in more detail below with reference to Fig. 15 .
  • the length 116 (denoted by the double-headed arrow) is about 500 ⁇ m.
  • the dimensions of the chamber 102, inlet 104, and outlet 114 may be selected according to, for instance, the sweat rate of the subject.
  • the volume of the chamber 102 may be minimised in order to decrease the filling time. This may assist to ensure a minimal delay between actual sweat excretion and sensing/monitoring of the sweat droplets 112.
  • the volume of the chamber 102 may be in the range of 0.1-100 nl, such as 0.5-50 nl, e.g. 1-20 nl.
  • the volume of the chamber 102 may be minimised in various ways in order to minimise the time required to fill the chamber 102 with sweat. Such modifications may be, for instance, to the plate 110 delimiting the chamber 102.
  • Fig. 2 shows an example in which the chamber 102 tapers from the inlet 104 towards the outlet 114.
  • the volume of such a tapering chamber 102 will be less than, for example, a cylindrical chamber 102, such as that of the apparatus 100 shown in Fig. 1 , having the same height and base diameter dimensions.
  • sweat glands 108 tend to excrete in sweat bursts, each sweat burst being followed by a rest period in which the glands 108 are not excreting.
  • the sweat rate may be about six times larger than the average sweat rate. The reason is that in a time window of 180 seconds there is typically a sweat burst of 30 seconds and a rest period of typically 150 seconds, hence there is a factor of six between the average sweat rate and the sweat rate during a sweat burst.
  • the time to form the depicted sweat droplet 112 is about 12 seconds during the sweat burst of the sweat gland 108.
  • the upper surface of the plate 110 may be provided with a gradient, such as a topological and/or chemical gradient, for the purpose of releasing the sweat droplet 112 from the outlet 114 and transporting the sweat droplet 112 to the sensor, as will be discussed further herein below in relation to the fluid transport assembly.
  • the surface area of the sweat droplet 112, in contact with the upper surface of the plate 110, required for releasing the sweat droplet 112 from the outlet 114 may depend on the steepness of the chemical and/or topological gradient, and the volume of the sweat droplet 112.
  • Fig. 3 shows another example of how the volume of the chamber 102 maybe minimised.
  • the chamber 102 is partitioned into compartments, at least some of the compartments being fluidly connected to each other in order to permit the chamber 102 to be filled with sweat.
  • the compartments may be formed by pillars 120.
  • Such pillars 120 may form part of the plate 110, and in such an example may be formed by patterning, e.g. etching, the lower surface of the plate 110. Other suitable ways of forming such pillars 120 will be readily apparent to the skilled person.
  • the porous material 122 may further serve as a filter for species, such as aggregated proteins, which may otherwise block downstream components of the apparatus 100, such as the outlet 114 or the fluid transport assembly.
  • the porous material 122 may assist to prevent fouling of the apparatus 100 by certain sweat components and impurities.
  • the porous material may, for instance, be selected to have specific adsorption properties for proteins and other species which it may be desirable to remove from the sweat entering or being contained within the chamber 102. Removing such impurities may be advantageous due to lessening the risk of the impurities altering the surface properties in the fluid transport assembly, e.g.
  • the porous material may assist to mitigate the risk that such impurities impair the hydrophilic/hydrophobic balance required for release of the sweat droplets 112 from the outlet 114, and migration of the sweat droplets 112 to the sensor.
  • the porous material 122 comprises, or is, an incompressible frit-like material positioned adjacent the surface of the skin 106
  • the porous material 122 may prevent, partly due to its incompressibility, blockage by bulging of skin 106 into the chamber 102.
  • the apparatus 100 may comprise a tapering chamber 102 which is also partitioned into compartments, e.g. by inclusion of a pillared structure 120 and/or a porous material 122.
  • the apparatus 100 comprises a fluid transport assembly which is arranged to enable release of the sweat droplet 112 protruding from the outlet 114.
  • the fluid transport assembly may thus, for example, comprise a structure which detaches the sweat droplet 112, e.g. the hemispherical sweat droplet 112, from the outlet 114.
  • a formed sweat droplet 112 may be anchored to the bulk of sweat which has filled the chamber 102 due to the attractive intermolecular forces between the water molecules in the sweat.
  • the sweat droplet 112 does not have a single contact angle value, but rather a range from a maximum to a minimum contact angle, which are called the advancing contact angle and the receding contact angle, respectively.
  • the difference between the advancing and receding contact angles is known as contact angle hysteresis.
  • the fluid transport assembly enables these forces to be overcome, such as to detach the sweat droplet 112 (and transport the sweat droplet 112 downstream towards the sensor).
  • the fluid transport assembly may be configured to enable a well-defined dislodgement of the sweat droplet 112 from the chamber 102. In other words, detachment of the sweat droplet 112 ensures unambiguous discrete sweat droplet 112 definition.
  • the detachment or release of the sweat droplet 112 may in some examples occur at the moment that the sweat droplet 112 reaches a certain diameter. At that diameter, an active and/or a passive gradient, e.g. which may be experienced by at least part of, and preferably the entirety of, the sweat droplet 112, may be sufficiently large to overcome the contact angle hysteresis of the sweat droplet 112, such that the sweat droplet 112 is released from the outlet 114.
  • the upper surface of the plate 110 is provided with a series of discrete electrowetting tiles 124.
  • the electrowetting tiles 124 may comprise an electrode which is coated with a hydrophobic material, such as a fluoropolymer.
  • the transport assembly may comprise an electric field generator (not shown) for charging and discharging each of the electrowetting tiles 124 of the series in sequence. Charging of an electrowetting tile 124 may cause the surface properties of the electrowetting tile 124 to switch from hydrophobic to hydrophilic, thereby to instantaneously overcome the contact angle hysteresis of the sweat droplet 112.
  • the sweat droplet 112 may correspondingly migrate onto the charged electrowetting tile 124. Subsequent discharge of the charged electrowetting tile 124 and charging of the subsequent electrowetting tile 124 in the series may cause the sweat droplet 112 to migrate to the subsequent electrowetting tile 124, and so on. This sequence may be regarded as an "electrowetting wave".
  • the fluid transport assembly may employ a "passive" gradient to release the sweat droplet 112 from the outlet 114.
  • Passive in this context means, in general terms, that the fluid transport assembly does not actively apply a force in order to overcome the contact angle hysteresis of the sweat droplet 112.
  • the upper surface of the plate 110 may be provided with a chemical and/or topological gradient which enables detachment of the sweat droplet 112 from the outlet 114.
  • the topological gradient may be provided by the upper surface of the plate 110 being inclined, such that, when the apparatus 100 is orientated for use, the gradient of the incline spanning the sweat droplet 112 diameter is sufficiently large to overcome the contact angle hysteresis.
  • the chemical gradient may be provided by the surface having hydrophilic and hydrophobic moieties thereon, which moieties are arranged to provide a wettability gradient along the surface.
  • microfluidic channels functionalised with hydrophobic CH 3 -moieties (towards the skin 106) and hydrophilic OH-moieties (towards the sensor) maybe used to create a chemical gradient ( Morgenthaler et al, Langmuir; 2003; 19(25) pp 10459-10462 ).
  • the chemical gradient may be, for example, provided with hydrophilic/hydrophobic domains at the molecular level, such that the wettability gradient varies substantially continuously along the surface.
  • a chemical gradient may, for instance, be provided by grafted polymer chains functionalising the surface of the plate 110.
  • hydrophilic/hydrophobic domains of ⁇ m dimensions may be provided on the surface such as to provide a stepwise wettability gradient.
  • the domains are arranged to have a gradual change in distribution over the length of the surface in the direction of the sensor.
  • the fluid transport assembly comprises a further plate 128 which is separated from and opposes the plate 110 delimiting the chamber 102.
  • the further plate 128 may enable control to be exerted over the volume of the sweat droplet 112. This may be achieved, for instance, by the further plate 128 being separated from the plate 110 by a defined distance 130.
  • the sweat droplet 112 may increase in size until it makes contact with the further plate 128.
  • the sweat droplet 112 may become detached by "jumping" over to the further plate 128. This may be regarded as a further example of an interfacial tension method for detaching the sweat droplet 112 from the outlet 114.
  • the separation distance 130 between the plate 110 and the further plate 128 may be selected such that it is large enough to ensure that the diameter of the forming sweat droplet 112, e.g. hemispherical sweat droplet 112, is sufficiently large before contacting the further plate 128, i.e. the lower surface of the further plate 128 which opposes the upper surface of the plate 110.
  • the lower surface of the further plate 128 may be provided with a passive (e.g. chemical and/or topological) and/or active (e.g. via an applied pressure and/or an electric field) gradient for transporting the sweat droplet 112 towards the sensor, in the direction of the arrows 126.
  • a passive e.g. chemical and/or topological
  • active e.g. via an applied pressure and/or an electric field
  • the sweat droplet 112 may start to migrate via the gradient.
  • the separation distance 130 between the plate 110 and the further plate 128 may be selected to ensure that the diameter of the forming sweat droplet 112 is sufficiently large before contacting the further plate 128. This may assist to ensure immediate migration/transport of uniformly sized sweat droplets 112.
  • the lower surface of the further plate 128 is provided with electrowetting tiles 124.
  • the electrowetting tiles 124 and the electric field generator may be similar to the arrangement described above in relation to Fig. 5 .
  • migration of the sweat droplet 112 on the further plate 128 via the electrowetting tiles 124 may mean that sweat droplet 112 migration will occur when the next electrowetting wave reaches the sweat droplet 112 which has been released onto the further plate 128.
  • a sufficiently high electrowetting wave frequency may ensure transport/migration of sweat droplets 112 of relatively uniform size/volume to the sensor.
  • the size/volume of the sweat droplet 112 may be determined by both the electrowetting wave frequency and the separation 130 of the plate 110 and the further plate 128, i.e. since the sweat droplet 112 may grow in the period between electrowetting waves.
  • the fluid transport assembly may be configured to control the separation 130 between the plate 110 and the further plate 128. This may, for instance, be achieved by the fluid transport assembly comprising a mechanism which engages at least one of the plates 110, 128, which mechanism is configured to move at least one of the plates 110, 128 such as to adjust the separation of the plates 110, 128.
  • the control exerted over the mechanism may be manual and/or automatic.
  • the fluid transport assembly may, for example, control the separation 130 according to the sweat rate of the sweat gland 108.
  • the fluid transport assembly may include a controller configured to control the mechanism to move at least one of the plates 110, 128 according to a determined sweat rate, e.g. as detected by the sensor.
  • the fluid transport assembly may be configured to control the separation 130 in a dynamic manner.
  • the number of sweat droplets 112 transported to the sensor may be relatively low. This issue may be alleviated by decreasing the separation 130 in order to increase the number of (smaller) sweat droplets 112 formed on the further plate 128.
  • Fig. 7 shows an example in which sweat droplet 112 detachment is achieved with a fluid transport assembly in which the upper surface of the plate 110 and the lower surface of the further plate 128 are both provided with a passive gradient, e.g. a chemical and/or topological gradient.
  • the arrows 126A and 126B respectively denote the direction of the gradient provided on the upper surface of the plate 110 and the lower surface of the further plate 128 for transporting the sweat droplet 112 towards the sensor.
  • Defined sweat droplet 112 detachment may alternatively or additionally be achieved by the fluid transport assembly applying a pressure gradient to the sweat droplet 112 protruding from the outlet 114. This may be considered as an example of providing an active gradient in order to overcome the contact angle hysteresis of the sweat droplet 112, since the fluid transport assembly actively applies a pressure/force to the sweat droplet 112 in order to overcome the contact angle hysteresis of the sweat droplet 112.
  • the pressure gradient may, for example, be applied by contacting the protruding sweat droplet 112 with a flow of carrier fluid.
  • the carrier fluid is preferably a fluid with which the sweat droplet 112 is immiscible.
  • the sensor may be able to detect each discrete sweat droplet 112 being carried thereto by the carrier fluid.
  • Suitable examples of such a carrier fluid include oils that do not absorb moisture, i.e. have relatively low or negligible hygroscopicity, such as oxycyte.
  • Oxycyte is a perfluorocarbon compound which is commonly used as a blood replacement.
  • a further plate 128 may be provided opposing the plate 110 delimiting the chamber 102, as previously described.
  • the sweat droplet 112 may form and grow until the sweat droplet 112 makes contact with the further plate 128, whereupon the sweat droplet 112 may block the passage defined by the space between the respective plates 110, 128.
  • the sweat droplet 112 may then be displaced by the flow of carrier fluid.
  • relatively uniformly sized sweat droplets 112 may be afforded; their size being determined by the distance 130 between the plates 110, 128, as previously described in relation to Fig. 6 .
  • the flow of carrier fluid may further assist in transporting the sweat droplets 112 to the sensor.
  • the fluid transport assembly may be configured to induce pulses or peaks in the flow rate, which pulses may provide sufficient pressure to release the sweat droplet 112 from the outlet 114.
  • a piezoelectric pump may, for instance, be used to induce such peaks in the flow rate of the carrier fluid. This may be straightforwardly achieved by varying the pulse frequency of the pump.
  • This structure may be considered as a passive supporting structure, and can be termed a "stalk" structure, with the outlet 114 being positioned atop the stalk, which stalk delimits the neck of the chamber 102.
  • this structure may assist with sweat droplet 112 detachment, particularly when utilising an active pressure gradient.
  • this supporting structure may be advantageously used in the context of the active pressure gradient between the plate 110 and the further plate 128, as described above in relation to Fig. 7 .
  • This contoured "stalk" structure may be fabricated in any suitable manner.
  • micromachining techniques such as deep reactive ion etching (DRIE), lithography, electroplating and molding (LIGA), wet etching, fused deposition modelling (FDM), projection micro-stereo-lithography, and direct-write additive manufacturing, maybe employed ( KS Teh. Additive direct-write microfabrication for MEMS: A review. Front. Mech. Eng. 2017; 12(4):490-509 ).
  • the sweat droplet 112 is transported via the fluid transport assembly to the sensor, e.g. a sweat rate sensor and/or a biomarker sensor.
  • the sensor may, for example, comprise a cell through which the sweat droplet 112 may be transported.
  • the fluid transport assembly may effect transportation or migration of the sweat droplet 112 to and through the sensor.
  • the released sweat droplet 112 is transported at least as fast as the subsequent sweat droplet 112 protrudes from the outlet 114.
  • migration of a sweat droplet 112 is faster than formation, i.e. the protruding, of the subsequent sweat droplet 112. This is in order to ensure unambiguous sweat droplet 112 definition, i.e. to ensure transport of a train of discrete sweat droplets 112 to the sensor.
  • the fluid transport assembly may maintain the discrete droplet characteristics of the sweat droplets 112 by ensuring rapid transport/migration relative to sweat droplet 112 formation. This may have advantages over a continuous flow of sweat, especially at low sweat rates, in terms of lessening or avoiding diffusion of components, such as biomarkers, between sweat samples collected at different points in time.
  • the biomarker concentration in each sweat droplet 112 may be primarily or solely determined by the size/volume of the sweat droplet 112, which leads to relatively straightforward measurement, as will be described further herein in relation to Fig. 15 . Accordingly, when the sensor to which the train of discrete sweat droplets 112 is transported is configured to enable detection of the concentration of a biomarker in the respective sweat droplets 112, the biomarker concentration as a function of time may be determined, with less possibility of error associated with diffusion of biomarkers between sweat sampled at different points in time. Such accumulation effects may otherwise lead to a lower biomarker concentration being measured than the actual concentration in sweat sampled during a particular time period. Thus, the apparatus 100 may offer a means of overcoming a key disadvantage of conventional continuous flow sweat monitoring.
  • Sweat glands 108 operate in a cyclic manner.
  • the sweat glands 108 typically excrete for typically 30 seconds during a sweat burst period, followed by a rest period of about 150 seconds.
  • the capability of the apparatus 100 to enable determination of detailed information concerning biomarker concentrations as a function of time, by virtue of the discretised flow of sweat droplets 112 supplied to the sensor by the fluid transport assembly, may apply even during the sweat burst period of a sweat gland 108.
  • the sweat gland bursts may correspondingly be detected, which may have various advantages, including the capability to determine lactate concentrations as will be described in more detail herein below with reference to Figs. 29 and 30 .
  • the relatively rapid transport of the sweat droplets 112 to the sensor via the fluid transport assembly may also assist to alleviate/minimise the problem of evaporation of the sweat as it migrates to the sensor. Such evaporation can, in the most severe case, prevent the sweat droplet 112 from reaching the sensor. Ensuring minimal evaporation of the sweat droplets 112 is especially important at low sweat rates/volumes.
  • the fluid transport assembly may be provided with a passive and/or active gradient for transporting the detached sweat droplet 112 to the sensor.
  • transport of the sweat droplet 112 may be via an interfacial tension technique and/or by application of pressure, as will be further described herein below.
  • a notable advantage associated with the passive gradient is that no power is required to be supplied to the fluid transport assembly for transporting the discrete sweat droplets 112 to the sensor.
  • the length of the chemical gradient trajectory may be restricted on one hand by the limited range in hydrophilicity/hydrophobicity balance reaching a lower contact angle of about 20° and an upper contact angle of 170°, and on the other hand by the size of the sweat droplet 112 being transported/migrated.
  • Smaller sweat droplets 112 may require a steeper gradient than larger sweat droplets 112.
  • relatively small sweat droplets 112 necessitate steeper gradients in order to initiate movement of the sweat droplet 112, due to the relatively small length of the sweat droplet 112 effectively restricting the exposure of the sweat droplet 112 to the gradient.
  • Transport distances of, for example, 5-10 mm are achievable and, in principle, are sufficient in practical terms for the apparatus 100 to function, depending on the size of the sweat droplets 112.
  • the chemical gradient may be formed in various ways.
  • a stepwise chemical gradient may, for instance, be employed.
  • the domains are arranged to have a gradual change in distribution over the length of the surface in the direction of the sensor.
  • Such a stepwise gradient may, for example, be fabricated from hydrophobic domains formed of nanopillars and hydrophilic domains formed of siloxy species.
  • the chemical gradient may result in contact angles between about 15° to about 166°, which are typical for superhydrophilicity and superhydrophobicity.
  • the chemical gradient may be provided with hydrophilic/hydrophobic domains at the molecular level, such that the wettability gradient varies substantially continuously along the surface.
  • a chemical gradient may, for instance, be provided by grafted polymer chains functionalising the surface of the plate 110, as discussed above in relation to detachment of the sweat droplet 112.
  • Fig. 9 schematically depicts an exemplary apparatus 100 in which the fluid transport assembly is provided with a passive topological gradient.
  • the topological gradient is provided by an inclined surface 138.
  • the inclined surface 138 inclines, i.e. climbs, towards the outlet 114, such that, when the apparatus 100 is orientated for use, e.g. horizontally as shown, the sweat droplet 112 is transported down the inclined surface 138 in the direction of the sensor.
  • the electrowetting tiles 124 may instead be arranged on a lower surface of a further plate 128 positioned opposite the outlet 114.
  • the size/volume of the sweat droplets 112 may depend on the distance 130 between the outlet 114 and the further plate 128, and thus the size/volume of the sweat droplets 112 may be independent of the period between the electrowetting waves, as previously described.
  • the counted number of sweat droplets 112 in a particular time period may be sufficient in this case to assess the sweat rate unambiguously, since the volume of the sweat droplet 112 is known a priori.
  • measuring sweat rate via discretised sweat flow may enable more precise measurement of the sweat flow rate, particularly at relatively low sweat rates.
  • flow rate sensors in conventional systems in which the sweat is transported as a continuous flow may have comparatively greater difficulty in precisely determining the sweat flow rate, particularly when the sweat flow rate is low.
  • a thermal sweat rate sensor of the type mentioned above may, for example, have difficulty in measuring low flow rates accurately due to heat diffusion.
  • Other known techniques, such as sensing the cumulative change in dielectric value may also have relatively low accuracy, and may require an additional sensor, such as a sodium sensor in order to establish the sweat rate per gland.
  • the apparatus 100 is arranged to collect sweat from four collection areas on the skin 106.
  • the apparatus 100 comprises twenty-five chambers 102 of the type shown in Fig. 17 per collection area.
  • each inlet 104 of the chambers 102 has a diameter of 360 mm (Example 1), leading to an area of each inlet 104 of 0.1 mm 2 .
  • the twenty-five chambers 102 there will be typically twenty-two or twenty-three chambers 102 which do not receive sweat from any sweat glands 108. In some exceptional cases there will be a chamber 102 which collects sweat from two or more sweat glands 102 (with a probability of around 1 in 200).
  • a chamber 102 receives sweat from a single sweat gland 108
  • that sweat gland 108 may exhibit an average sweat rate of 0.2 nl/min, with the sweat rate during a sweat burst 192A, 192B of about 1.2 nl/min (assuming a typical burst period 192A, 192B lasts about 30 seconds burst, and a rest phase 194A, 194B lasts around 150 seconds).
  • a sweat droplet 112 may then protrude from the outlet 114, as schematically depicted in Fig. 17 .
  • Sweat glands 108 which are relatively close to each other may receive nerve pulses which activate them at the same time. However, the time taken for the metabolism required for the pumping effect of the sweat gland cells to be exhausted may vary between the sweat glands 108, so partially overlapping cycles may occur.
  • Fig. 19 shows graphs of sweat rate versus time (upper pane), and sensor signal versus time (lower pane) when respective sweat glands 108 have sweat bursts 192A, 192B, 198A, 198B at different times with respect to each other.
  • one sweat gland 108 supplies a first chamber 102, and a different sweat gland 108 supplies a second chamber 102.
  • the sweat droplets 112 derived from the respective glands 108 may be distinguished from each other by, for example, analysis of the sensor 166 data.
  • the possibility of periods 200, 202, and 204 corresponding to rest periods may be excluded, since these periods 200, 202, 204 are significantly shorter than a typical rest period, which may be around 150 seconds as previously described.
  • the periods denoted as 194A and 206A have durations typical of rest periods, these may be correspondingly identified as rest periods 194A, 206A of respective sweat glands 108.
  • the sweat rate dependence of particular biomarkers may only occur during the (active) sweat burst period of the sweat gland 108, and clearly not in the rest period.
  • the primary sweat production and resorption leading to sweat excretion onto the skin 106 may only occur during the sweat burst period.
  • the ratio of the primary sweat gland rate divided by the resorption rate of sweat rate dependent biomarkers may only change as a function of sweat rate. The duration of the sweat burst may not therefore influence the sweat rate. Ramping up and down will, however, influence the sweat rate, as will be discussed further herein below.
  • sweat droplets 112 derive from two sweat glands 108 excreting sweat into respective chambers 102, but the sweat droplets 112 exactly coincide with each other. This has the effect that the time taken for each of the coalesced sweat droplets 112 to pass through the sensor 166, as shown in Fig. 20 by the width of each of the sensor signals, is increased from 0.196 seconds for a single sweat droplet 112 (see Fig. 18 above) to 0.224 seconds.
  • sweat droplets 112 derive from two sweat glands 108 excreting sweat into respective chambers 102.
  • Signals 222A-222E are assigned to a first sweat gland 108
  • signals 223A-223E are assigned to a second sweat gland.
  • Such a sensor signal pattern may be ascribed to each sweat gland 108 producing a set of five sweat droplets 112, shifted in time.
  • An alternative explanation would require a very erratic behaviour of one sweat gland 108, which is physiologically unlikely, i.e. an oscillating sweat rate during a sweat burst. The latter may correspondingly be ruled out.
  • a sweat droplet 112 may migrate towards the sensor 166 approximately every 6 seconds, and within one sweat burst lasting 30 seconds there will be five sweat droplets 112 formed. This may be followed by a rest period of about 150 seconds during which no sweat droplets 112 may be formed. This pattern may then be repeated. When two sweat glands 108 are active, two of these patterns will occur. Note that this discussion is confined to two chambers 102, each chamber 102 receiving sweat from a respective sweat gland 108. The case of a chamber 102 receiving sweat from more than one sweat gland 108 will also be discussed herein below.
  • the processor may straightforwardly identify the respective patterns, and the sweat rate per gland may be straightforwardly derived from the data pattern, e.g. as in the scenario described above with reference to Fig. 19 .
  • Sweat droplets 112 of individual sweat glands 108 may thus be distinguished by considering the cyclic behaviour (sweat burst and rest periods) of the sweat glands 108. Even in the case that the sweat bursts are assigned incorrectly, there may be no effect on the determined average sweat rate per gland, as previously described.
  • the processor may be configured to search for the cyclic behaviour of the sweat gland or sweat glands 108, and identify which sweat droplets 112 derive from which sweat gland or sweat glands 108. This may enable the processor to determine the number of sweat glands, and the sweat rate per gland.
  • the sweat droplets are sensed using the sensor during a time period.
  • Step 230 may, for instance, be implemented using the sensor 166 described above.
  • the sweat droplets are counted during a time period in step 232.
  • time intervals between consecutive sensed sweat droplets during the time period are determined. The time interval may correspond to the period between a sensor signal returning to the baseline and a subsequent increase from the baseline of a subsequent sensor signal.
  • a measure of the volume of each of the counted sweat droplets is received at step 236, e.g. from the sensor, as previously described.
  • the active i.e. sweat burst, periods of the one or more sweat glands during which the one or more sweat glands are excreting sweat, and the rest periods of the one or more sweat glands during which the one or more sweat glands are not excreting sweat, are identified, and the active and rest periods are assigned to the one or more sweat glands.
  • This identification and assignment uses the time intervals and the measure of the volume of each of the counted sweat droplets, as previously described with reference to Figs. 19-22 .
  • the number of sweat glands to which the active and rest periods are assigned is determined.
  • the sweat rate per gland is then determined at step 242. This determination of the sweat rate per gland uses the number of sweat droplets, the measure of the volume of each of the counted sweat droplets, and the determined number of sweat glands.
  • Fig. 24 shows an example of an algorithm 243 which may be employed in order to identify the sweat burst and rest periods of the one or more sweat glands, and assign the sweat burst and rest periods to the one or more sweat glands.
  • the algorithm 243 shown in Fig. 24 may be employed, for example by the processor of the system, to implement step 238 of the method 224.
  • the sensor signals i.e. data pattern
  • a defined time period e.g. 10 minutes
  • the received data is fitted to a template model.
  • the fitting takes into account: the number of sensor signals, i.e. pulses, sensed in the time period, the width of each of the sensor signals, i.e. the pulse width, which may be a measure of the volume of each sensed sweat droplet, and the time intervals between consecutive sensor signals.
  • the model fitting also takes physiologically reasonable sweat burst and rest periods into account.
  • the goodness of fit of the received data to the template model is determined.
  • at least some of the data is identified as being suitable for basing the sweat rate determination thereon. This identification may be made on the basis of the goodness of fit of this identified data reaching or exceeding a predetermined threshold.
  • the fraction of the originally received data corresponding to the identified data is determined, and if this fraction is sufficiently high, the algorithm ends at 256. If, on the other hand, this fraction is below a predetermined value, e.g. 80%, then a new fitting is implemented in block 254, and blocks 246 to 252 are repeated, i.e. thereby to perform an iteration.
  • the algorithm starts with a template of (i) the number of sweat droplets in a sweat burst, (ii) the pulse time, (iii) the time during which the sweat droplet passes through the sensor, (iv) the duration time of a sweat burst period and (v) the duration time of a rest period.
  • each part of the data set that sufficiently resembles this template model is subtracted from the originally received data.
  • the goodness of fit criterion may be used to control how much of the received, i.e. real, data may deviate from the model. If, by such a subtraction, a wide pulse is partially removed, the remaining pulse remains in the data set. Such a remaining pulse may, for instance, be subsequently assigned to another sweat gland.
  • Each part of the data set that resembles this template may again be subtracted and the process is again repeated. Further repetition of the algorithm may not be required since overlap of sweat droplets respectively originating from four glands is highly unlikely.
  • the size of the remaining data set is evaluated, and if, for example, this is larger than 5 to 20% of the original data set, a new iteration is started with new values for the fitting parameters. In this manner, data patterns with are not overlapping as well as overlapping data patterns may be reliably evaluated, thereby enabling the average sweat rate per gland to be determined.
  • the fitting parameter space may be correspondingly limited.
  • the volume of each of the sweat droplets 112 which are released from the outlet 114 of the chamber 102 is defined by the distance 130 between the outlet 114 and the opposing surface of the further plate 128, as previously described.
  • the sweat droplets 112 may have different sizes/volumes, particularly during the ramp up and ramp down phases of a sweat burst. This may necessitate a more complex implementation of step 238, for example using a more complex model where the pulse time is variable. Alternatively, a template may be used which neglects the edges, i.e. ramp up and ramp down phases, of a sweat burst in the analysis.
  • a single patch may include four apparatuses 100, with each apparatus 100 having twenty-five chambers 102.
  • the number of apparatuses 100, and thus chambers 102, may be varied, for example, in accordance with the required precision, since sweat sampled from a greater number of sweat glands may lead to a decreasing variation in the determined average sweat rate per gland.
  • Fig. 20 shows the highly unlikely scenario in which the respective sweat droplets 112 originating from sweat bursts of different sweat glands 108 exactly coincide with each other, such that only one sensor signal pattern results.
  • sweat droplets 112 having a predetermined volume are transported by the apparatus 100 to the sensor 166, sweat droplets 112 having a larger sensed volume than the predetermined volume must be caused by coalescence of sweat droplets 112 originating from respective sweat glands 108, as previously described.
  • larger sweat droplets 112 may either be caused by coalescence of sweat droplets 112 or by a higher sweat rate (recall that in this example the diameter of the hemispherical sweat droplet may vary between 77 ⁇ m and 124 ⁇ m, depending on the sweat rate per gland).
  • the coalescent (hemispherical) sweat droplet 112 volume at the lowest average sweat rate of 0.2 nl/min/gland may have a diameter of about 97 ⁇ m. At first glance, this may be ascribed to a single sweat gland 108 excreting sweat at an average sweat rate of 2.5 nl/min/gland.
  • the excretion cycles of sweat glands 108 may vary. For example, this may mean that the duration of the rest period may vary. Consequently, the algorithm may evaluate sensor signal patterns, and in particular the intervals between sensor signals, taking this variability of the rest periods into account.
  • sweat glands 108 may become active as the sweat rate increases.
  • the algorithm may account for such sweat gland 108 activation.
  • the system may, for instance, be configured on the assumption that one hundred active sweat glands are present per cm 2 . This relatively high estimate may account for activation of further sweat glands 108 at elevated sweat rates.
  • the exemplary apparatus 100 shown in Fig. 6 may provide well-defined separation of sweat droplets 112, even when the sweat rate is relatively high (e.g. 5 nl/min/gland).
  • a sweat droplet 112 will be transported to the sensor every second, and within a sweat burst lasting 30 seconds, there will be thirty sweat droplets 112 formed. No sweat droplets 112 will be formed during the subsequent rest period, e.g. during the subsequent 150 second period. Since each incremental step of the electrowetting wave may last 0.1 seconds, the sweat droplets 112 may be clearly separated from each other, as previously described. Consequently, the same analysis method may be applied as when the sweat rate is relatively low.
  • Fig. 25 shows a graph of the sweat rate sensor signal as a function of time when the sweat rate is relatively high.
  • the average sweat rate is 5 nl/min/gland
  • the sweat burst period lasts 30 seconds
  • the rest period lasts 150 seconds.
  • the delay between the onset of a burst and the first sensor signal is ascribed to the time taken for a sweat droplet 112 to be formed (1 second during the sweat burst in this case), and the time taken for transport of the sweat droplet 112 to the sensor 166 (7 seconds in this case; since the migration speed is 700 ⁇ m per second, and the distance between the chamber 102 and the sensor 166 is 5 mm).
  • thirty sweat droplets 112 are formed during the 30 second sweat burst.
  • the width of each sensor signal is 0.26 seconds (hemispherical sweat droplet 112 having a diameter of 124 ⁇ m; the width of the sensor 166 being 60 ⁇ m; dividing the combined length 184 ⁇ m by the migration speed of 700 ⁇ m per second).
  • a system comprises four apparatuses 100, with each apparatus 100 having twenty-five chambers 102.
  • a sweat rate sensor 166 is provided for each of the four apparatuses 100.
  • the system has a total of one hundred chambers 102.
  • the probability of no sweat gland 108 excreting into a chamber 102 P0
  • the probability of one sweat gland 108 excreting into a chamber 102 P1
  • the probability of two or more sweat glands 108 excreting into a chamber 102 P ⁇ 2
  • the occurrence of two glands or more will be 1 in 18.
  • the requirement that four chambers 102 receive sweat from a single sweat gland 108 may be relaxed, for example to two chambers 102 receiving sweat from a single sweat gland 108. In this case, the chance of violating the requirement would be 9 in 10000.
  • Fig. 26 shows graphs of the sweat rate sensor signal as a function of time when the sweat droplet 112 derives from one sweat gland 108 per chamber 102 (upper pane), and when the sweat droplet 112 derives from two sweat glands 108 per chamber 102 (lower pane). It is noted that the latter scenario is distinctly different from the scenarios depicted in Figs. 19-21 in which sweat droplets 112 derive from two sweat glands 108 excreting sweat into respective chambers 102.
  • the sweat rate of one sweat gland 108 corresponds to the sensor signal pattern in the upper pane of Fig. 26
  • one of the two sweat glands 108 excreting into the same chamber 102 may be located close to the sweat gland 108 excreting into the single chamber 102. This is on the assumption that sweat glands 108 which are local to one another may excrete sweat at a similar or the same rate.
  • the sensor signal pattern as depicted in the lower pane could be attributed to a single gland excreting sweat into a chamber 102 with a sweat rate of 0.4 nl/min/gland.
  • this interpretation may be ruled out.
  • the two sweat glands 108 excreting into a common chamber 102 as depicted in the lower pane of Fig. 26 are shown as executing a sweat burst at the same time. This may be reasonable, since the respective sweat glands 108 may be relatively close to each other, and nerve pulses may reach the two sweat glands 108 at the same time and with the same intensity.
  • a sweat droplet 112 pattern may result in which, for instance, at the start and the end of the sweat burst, the sensor signals are spaced by 6 seconds, and during the sweat burst, the sensor signals are spaced by 3 seconds (see, e.g., Fig. 22 ). This would immediately point to two non-synchronised excreting sweat glands, and may be straightforwardly recognised.
  • the droplet pattern event of two sweat glands 108 excreting into a common chamber 102 may be analysed by the algorithm shown in Fig. 24 , except that in block 246 the algorithm initially fits the data pattern to a model template based on a single sweat gland 108 excreting into a chamber 102 ("lowest sweat droplet 112 count"), and then fits the data pattern to a second template model based on two sweat glands 108 excreting into a chamber 102 ("two times higher sweat droplet 112 count").
  • the sweat droplets 112 may be sensed, and their contact time with the sensor 166 may be determined using, for example, a capacitance and/or conductivity sensor, as previously described.
  • the conductivity sensor in particular, may assist in the determination of the sweat rate per gland.
  • This conductivity of the sweat droplets 112 may be partly determined by the concentration of ions in the sweat droplet 112.
  • the sodium ion concentration in sweat may vary as a function of sweat rate from 0.06 to 0.76 g/100 ml.
  • the measured conductivity of the sweat droplets 112 may be used as a proxy for the sodium ion concentration.
  • a specific electrochemical sensor for sodium may be employed, providing the response speed of the sensor is sufficiently fast to sense the sodium concentration of a passing sweat droplet 112.
  • the following three scenarios may be considered: one sweat gland 108 excreting into a chamber 102 with a sweat rate of 5 nl/min/gland; two sweat glands 108 excreting into a chamber 102, e.g. synchronously, with each sweat gland 108 excreting at a rate of 2.5 nl/min/gland; and three sweat glands 108 excreting into a chamber 102, e.g. synchronously, with each sweat gland 108 excreting at a rate of 1.67 nl/min/gland.
  • a sweat rate sensor solely relying on counting the sweat droplets 112 and determining the time taken for each sweat droplet 112 to pass through the sensor 166 may not be able to distinguish between these situations because the sensor signal patterns will be the same in each of the scenarios.
  • an algorithm of the type described above may be employed or, alternatively, a sensing device for detecting a parameter relating to the concentration of an analyte whose concentration varies as a function of the sweat rate may be employed.
  • a conductivity sensor may be employed for this purpose, in which case the parameter is the conductivity, and the analyte is a sodium ion.
  • the step of identifying 238 the one or more sweat glands 108 may also be based on the measured concentration of the analyte, e.g. via a conductivity measurement.
  • the following additional pair of scenarios may also be considered: one sweat gland 108 excreting into a chamber 102 at a sweat rate of 5 nl/min/gland; and two sweat glands 108 excreting into a chamber 102, e.g. synchronously, with each sweat gland 108 excreting at a rate of 5 nl/min/gland.
  • the sweat rate sensor may sense a sweat droplet 112 every second, and in the second scenario the sweat rate sensor may sense a sweat droplet 112 every half second.
  • the sensor signal pattern being interpreted as indicating that in the first scenario only one sweat gland 108 is excreting into a chamber 102, and in the second scenario there are two sweat glands 108 excreting into the same collection chamber 102.
  • an alternative interpretation would be that in the first scenario only one sweat gland 108 is excreting into a chamber 102, and in the second scenario there is also one sweat gland 108 excreting into the chamber 102 but at twice the sweat rate with respect to the first scenario.
  • the second situation would seem unlikely, since local sweat glands 108 do not tend to exhibit such substantially different sweat rates from a physiological perspective, by detecting the parameter relating to the concentration of an analyte whose concentration varies as a function of the sweat rate, e.g. conductivity, an unambiguous interpretation may be attained.
  • the first interpretation will lead to the ionic concentrations being measured in the respective scenarios being equal, whereas the second interpretation will lead to different ionic concentrations being measured, so only one of these interpretations may be consistent with the measured parameter.
  • the following further pair of scenarios may also be considered: one sweat gland 108 excreting into a chamber 102 at a sweat rate of 5 nl/min/gland; and two sweat glands 108 non-synchronously excreting into the same chamber 102, each sweat gland 108 excreting at a sweat rate of 2.5 nl/min/gland.
  • the start of an electrowetting wave may not be synchronised with the onset of a sweat burst. This issue has significance in the case of the example shown in Fig. 17 , in which the electrowetting tiles 124 are provided on the upper surface of the plate 110 delimiting the chamber 102. Sweat droplets 112 may be detected which have different sizes/volumes at the ramp up and ramp down phases of the sweat burst than during the intervening period of the sweat burst. An electrowetting wave may be initiated every second, as previously described.
  • the sweat burst may begin at some point during this second, such that the size/volume of the first sweat droplet 112 transported to the sensor 166 may be smaller than subsequent sweat droplets 112 which have formed during the entire second between successive electrowetting waves.
  • the latter may be regarded as "fully formed” sweat droplets 112, whereas the smaller sweat droplets 112 produced during ramp up or ramp down of the sweat burst may be regarded as being "partially formed”.
  • a sweat droplet 112 may be too small to overlap both of the electrowetting tiles 124 partially delimiting the outlet 114. As such, this sweat droplet 112 may not be transported to the sensor 166. But after six electrowetting waves, and assuming an average sweat rate of 0.2 nl/min/gland, the sweat droplet 112 may have grown sufficiently large to partially overlap these two electrowetting tiles 124.
  • the total time for sweat droplet 112 growth may be 5.5 seconds, and such a sweat droplet 112 may be correspondingly smaller than a sweat droplet 112 that formed during the full 6 seconds.
  • the forming sweat droplet 112 may start to overlap the electrowetting tiles 124 partly delimiting the outlet 114 after about 0.2 seconds.
  • a partially formed sweat droplet 112 which migrates to the sensor may be substantially smaller than a fully developed sweat droplet 112.
  • Fig. 27 shows a graph of the sweat rate as a function of time with a schematic depiction of the frequency of the electrowetting wave 260 when the latter is not synchronised with sweat droplet 112 formation (upper pane), and a graph of the associated sweat rate sensor signal as a function of time (lower pane).
  • the average sweat rate is 5 nl/min/glands
  • commencement of the sweat burst 192A precedes the electrowetting wave 260 by 0.2 seconds, such that the first sweat droplet 112 had only 0.2 seconds in which to form, before being transported to the sensor 166. This is reflected in the shorter time (0.19 seconds) taken for the first sweat droplet 112 to pass through the sensor 166, as compared with the sweat droplets 112 which have formed during the entire second between consecutive electrowetting waves 260 (0.26 seconds).
  • the last sweat droplet 112 had 0.8 seconds to form, and this is reflected in the shorter time taken for this sweat droplet 112 to pass through the sensor 166 (0.25 seconds) than the sweat droplets 112 which formed during the entire second between electrowetting waves 260 (0.26 seconds).
  • Fig. 28 shows graphs analogous to those shown in Fig. 27 , but with more pronounced ramps up and down at the start and end of the sweat burst respectively.
  • the ramps were assumed to be fast with respect to the 1 second cycle of the electrowetting arrangement 144.
  • the ramp up and ramp down takes about 5 seconds. In this case, the sweat rate during ramp up and ramp down is less than in the middle of the sweat burst.
  • the contact time of the first sweat droplet 112 is greater than that of the last.
  • the partial sweat droplet 112 formed at ramp down is too small to be transported to the sensor 166, and will likely be migrated in the subsequent sweat burst. This partial sweat droplet 112 may combine with newly formed sweat received during a subsequent sweat burst, which would mean that there is no missing sensor signal at the ramp up during this subsequent sweat burst.
  • the sweat droplets 112 may all be of similar (predetermined) size.
  • the sweat droplets 112 may emerge more slowly, and the intervals between successive sweat droplets 112 may be larger than between consecutive sweat droplets 112 produced mid-burst. If larger sweat droplets 112 are sensed, these will have resulted from coalescence of sweat droplets 112 originating from different sweat glands 108 excreting into respective chambers 102.
  • a system comprises three apparatuses 100, which each have three chambers 102.
  • a sweat rate sensor 166 is provided for each of the three apparatuses 100.
  • the system has a total of nine chambers 102.
  • Each of the chambers 102 has a circular inlet 104 with a diameter of 1130 ⁇ m and a circular outlet 114 with a diameter of 33 ⁇ m (see Example 2 above).
  • each inlet 104 With the area of each inlet 104 being 1 mm 2 , the probability of no sweat gland 108 excreting into a chamber 102 (P0) is 36.8%, the probability of one sweat gland 108 excreting into a chamber 102 (P1) is 36.8%, the probability of two sweat glands 108 excreting into a chamber 102 (P2) is 18.4%, the probability of three sweat glands 108 excreting into a chamber 102 (P3) is 6.1%, and the probability of four or more sweat glands 108 excreting into a chamber 102 (P ⁇ 4) is 1.9% (see Table 1 above).
  • the sensor signal patterns resulting from one or more sweat glands 108 may be suitably distinguished, such that the average sweat rate per gland may be determined, as previously described. In this case, however, there may be more incidences of two or more sweat glands 108 excreting into the same chamber 102 than in the example described above.
  • the potential drawback is that in a very small number of cases, there may be four or five sweat glands 108 excreting sweat into the same chamber 102. This may result in a particularly complex overlapping data pattern, but with the help of a suitable criterion in the algorithm, the result can be declared invalid and the patch may be replaced accordingly.
  • each inlet 104 may be, for example, in the range of 0.05 mm 2 to 2 mm 2 , such as 0.75 mm 2 to 1.5 mm 2 . This may ensure that chamber(s) 102 receive(s) sweat from sweat glands 108, but not from so many sweat glands 108 per chamber 102 that interpreting the sensor signal patterns becomes overly complex.
  • the algorithm may be used as previously described, but the physical design of the system may be simpler than, for instance, the system having one hundred chambers 102.
  • the physical design of the system may be more complex, but the algorithm may be simplified by focussing on the data patterns corresponding to supply of a given chamber 102 by a single sweat gland 108. Less likely data patterns may be discarded.
  • each chamber 102 may be realistic to provide each chamber 102 with its own sweat rate sensor 166, for example a capacitance or conductivity sensor due to the relatively simple design of such sensors.
  • the algorithm may only serve the purpose of distinguishing between one or more glands 108 excreting into a particular chamber 102.
  • chambers 102 may be employed in order to handle variations in the sensed data.
  • the sweat gland density of one hundred sweat glands per cm 2 used in the present examples should be regarded as being for the purpose of explanation only.
  • the size and number of the chambers 102 can be adapted for the purpose of optimising the results. For example, when the apparatuses 100 are to be applied to skin locations where there are relatively few active sweat glands 108, the skin surface area for sampling may be correspondingly increased in order to obtain sufficient meaningful data.
  • Lactate is an important biomarker because it is produced by cells if oxygen deprivation occurs. Increased levels of lactate in blood is an indication of shock.
  • shock types There are four shock types: hypovolemic, obstructive, cardiogenic and distributive shock.
  • One of the causes of a distributive shock is sepsis. Shock and sepsis are serious disorders that are life threatening.
  • lactate concentration in sweat is highly desirable.
  • lactate concentration in sweat is sweat rate dependent
  • lactate is secreted by the sweat gland cells themselves.
  • transfer of biomarkers from blood to sweat can take up to about 10 minutes in the human body, although this is an acceptable delay from a clinical viewpoint.
  • the present disclosure thus far provides a solution to the first complication (i).
  • the majority (90-95%) of lactate excreted in sweat onto the skin may originate from the sweat glands themselves, with the remainder (5-10%) originating from the blood.
  • the lactate originating from sweat gland cells themselves and originating from blood should be differentiated in some manner.
  • Sweat gland cells are innervated with nerves, and nerve pulses activate the sweat glands.
  • metabolism causes interstitial fluid to be pumped into the coiled tubular section of the sweat gland.
  • the metabolism requires energy and consequently oxygen is consumed.
  • the nerve activity is relatively high, the produced sweat rate increases and greater quantities of oxygen are required. It is conceivable that oxygen depletion may cause the sweat glands to switch to an alternative (anaerobic) pathway, thereby producing lactate.
  • sweat glands produce sweat in sweat bursts (lasting about 30 seconds), each sweat burst being followed by a rest period (lasting about 150 seconds), it may be reasonably assumed that sweat gland cells produce lactate in an analogous cyclic fashion with a period in the order of about 180 seconds.
  • a clinically relevant increase in the lactate concentration in blood may have a significantly different time scale in the order of a few hours, e.g. 1-3 hours.
  • the different timescales associated with sweat gland-related and blood-related changes in lactate concentration in the sweat excreted onto the skin may be used to differentiate the former source of lactate from the latter. Accordingly, measuring the lactate concentration in sweat as a function of time may lead to suitable differentiation of sweat gland-derived and blood-derived changes in lactate concentration.
  • the senor 166 may include a lactate sensor (although if the concentration of another biomarker as a function of time is of interest, a biomarker sensor specific for that particular biomarker may be included in the sensor 166).
  • a biomarker sensor specific for that particular biomarker may be included in the sensor 166.
  • the lactate sensor may further sense the time taken for the sweat droplet 112 to traverse its detection surface. If the response time of the lactate sensor is insufficiently fast, a further sensor, e.g. a capacitance, impedance, conductivity and/or optical detector may be employed, as previously described.
  • a further sensor e.g. a capacitance, impedance, conductivity and/or optical detector may be employed, as previously described.
  • the fluid transport assembly is arranged to transport the sweat droplet at a speed of 700 ⁇ m per second.
  • the time taken for each sweat droplet 112 to traverse the lactate sensor may be about 0.19 to 0.29 seconds when the sweat droplets 112 are hemispherical, and 0.15 to 0.57 seconds when the sweat droplets 112 are shaped into beam-shaped sweat droplets 112 by the channel 168 of the sensor 166, as previously described with reference to Fig. 15 .
  • the sweat droplets 112 may be transported across the detection surface of the lactate sensor via a chemical gradient.
  • the speed of migration may be lowered as the sweat droplets 112 are being transported through the lactate sensor by employing a "lower power" chemical gradient than that employed by the fluid transport assembly upstream (and in some cases downstream) of the lactate sensor. This may be achieved by providing a smaller local hydrophilic-hydrophobic change per unit of length in the direction of the migration coinciding with the lactate sensor.
  • connection scheme A The following connection scheme may thus be used in order to transport the sweat droplet 112 at a constant velocity across the series of electrowetting tiles 124 labelled 1 to 32.
  • connection scheme A As shown in the upper pane of Fig. 29 (connection scheme A), tile 1 is connected to tiles 9, 17, 25; tile 2 is connected to tiles 10, 18, 26; tile 3 is connected to tiles 11, 19, 27; tile 4 is connected to tiles 12, 20, 28; tile 5 is connected to tiles 13, 21, 29; tile 6 is connected to tile 14, 22, 30; tile 7 is connected to tile 15, 23, 31; and tile 8 is connected to tile 16, 24, 32.
  • An electrowetting wave may be created by, for example, the electric generator implementing the following sequence: charging tile 1 (and all connected tiles); waiting 0.1 seconds; discharging tile 1 (and all connected tiles) and simultaneously charging tile 2 (and all connected tiles); waiting 0.1 seconds; discharging tile 2 (and all connected tiles) and simultaneously charging tile 3 (and all connected tiles); waiting 0.1 seconds; discharging tile 3 (and all connected tiles) and simultaneously charging tile 4 (and all connected tiles); waiting 0.1 seconds; discharging tile 4 (and all connected tiles) and simultaneously charging tile 5 (and all connected tiles); waiting 0.1 seconds; discharging tile 5 (and all connected tiles) and simultaneously charging tile 6 (and all connected tiles); waiting 0.1 seconds; discharging tile 6 (and all connected tiles) and simultaneously charging tile 7 (and all connected tiles); waiting 0.1 seconds; discharging tile 7 (and all connected tiles) and simultaneously charging tile 8 (and all connected tiles); waiting 0.1 seconds; discharging tile 8 (and all connected tiles); waiting for 1 second and repeating the cycle.
  • each sweat droplet 112 may travel 70 ⁇ m every 0.1 seconds, which corresponds to a sweat droplet 112 speed of 700 ⁇ m per second. Since a 1 second time period separates consecutive cycles, the frequency of occurrence of the electrowetting waves is, in this specific example, 1 Hz.
  • connection scheme B shown in the lower pane of Fig. 29 is similar to that shown in the upper pane, but tile 1 is also connected to the tiles labelled A, tile 4 is also connected to the tiles labelled B, and tile 8 is also connected to the tiles labelled C. Tiles A, B and C are local to the lactate sensor. Note that the black dot 274 denotes an electrical connection, but an intersection 276 without a black dot means that there is no electrical connection.
  • Tile 1 is charged (together with the connected tiles, including tile A), there is a 0.1 second delay, and tile 1 is discharged (together with the connected tile) and tile 2 is simultaneously charged, and so on. Due to the local connection scheme, tile B is charged 0.4 seconds after tile A, and tile C is charged 0.4 seconds after tile B. Consequently, the migration velocity in the locality of the lactate sensor is decreased by a factor of four with respect to the connection scheme A shown in the upper pane of Fig. 29 .
  • the local velocity through the lactate sensor is thus one tile per 0.4 seconds, rather than one tile per 0.1 seconds. Consequently, the local average velocity of the sweat droplets 112 through the lactate sensor in this example is 175 ⁇ m per second.
  • the frequency at which the electrowetting waves are applied may still be 1 Hz, such that the risk of uncontrolled collision of sweat droplets 112 in the region of the lactate sensor, i.e. due to sweat droplets 112 catching up with one another, may be minimised. It should be noted that sweat droplets 112 which are less than 0.4 seconds apart will coalesce on tile A, but this may not pose difficulties since a one second resolution may be generally sufficient.
  • the detection surface of the lactate sensor spans the same area as tiles A-C, for instance by the detection surface of the lactate sensor being opposite the electrowetting tiles A-C, the contact time with the lactate sensor may be increased.
  • the time taken for each sweat droplet 112 to traverse the lactate sensor may be about 0.19 to 0.29 seconds when the sweat droplets 112 are hemispherical, and 0.15 to 0.57 seconds when the sweat droplets 112 are beam-shaped sweat droplets 112.
  • connection scheme B an electrowetting wave which transports the sweat droplets 112 four times slower
  • the shortest time for a sweat droplet 112 to pass through the lactate sensor may be prolonged to 0.60 seconds.
  • the total contact time of a sweat droplet 112 with the sensor may be 1.80 seconds. This is longer that the shortest response times of conventional lactate sensors.
  • connection scheme may be such that a step duration in the locality of the sensor 166 is not equal to or more than one second, because this may risk that sweat droplets 112 in the locality are caught up by sweat droplets 112 transported by an electrowetting wave with a cycle time of 1 second, and thereby cause uncontrolled sweat droplet 112 collisions to occur.
  • Repetition of the three local tiles (A, B and C) may further prolong the time taken for the sweat droplet 112 to pass through the sensor 166.
  • four consecutive sets of these three tiles (A B C A B C A B C A B C) in the connection configuration B may increase the time taken for the sweat droplet 112 to pass through the sensor 166 to 2.40 seconds.
  • the area of the detection surface is increased to span these 12 tiles, the contact time may be increased to 9.60 seconds.
  • the velocity may be increased again downstream of the sensor 166 by applying the first connection scheme A.
  • the contact time with the sensor 166 can be further increased.
  • a contact time of about 60 seconds may be achieved. Whilst increasing the cycle time of the electrowetting wave from 1 to 2 seconds, might at first glance appear to provide a means for increasing the contact time with the sensor 166, this would also cause growth of the sweat droplets 112, necessitating the use of larger tiles, which may negate the increase in the contact time.
  • the system may be correspondingly employed to measure the lactate concentration per sweat droplet 112.
  • the lactate concentration typically 5 to 30 sweat droplets per sweat burst of a sweat gland 108 may be transported to the lactate sensor.
  • the lactate concentration as a function of time may be determined.
  • lactate originating from the blood may remain virtually unchanged during a period of 3 minutes, whereas lactate produced by the sweat glands may change according to the 3 minute cycle time of the sweat glands.
  • the apparatus, systems and method of the present disclosure may enable the variation in the lactate concentration in sweat as a function of time to be closely monitored.
  • the present disclosure may enable the dynamics of lactate production in sweat glands to be observed with a relatively high degree of detail/resolution.
  • the dynamics of lactate production in sweat glands during a sweat burst is likely to be different from the virtually constant lactate concentration in sweat solely derived from the lactate in blood.
  • the respective time scales may be determined, and the lactate concentration in sweat derived from the lactate in blood may be determined.
  • the lactate concentration in sweat derived from the lactate in blood may be determined.
  • the lactate concentration in sweat may be determined. It may prove unnecessary to find an exact correlation, but increasing or decreasing trends in lactate concentration over time should correlate between blood and sweat.
  • the present disclosure may enable interrogation of lactate dynamics, which is a pre-requisite for verifying that time-scale-based differentiation of sweat gland-derived and blood-derived changes in lactate concentration is possible.
  • the model shown in the lower left pane of Fig. 30 shows that, during a sweat gland burst, the sweat glands cells produce an increasingly larger lactate concentration up to a certain maximum, and subsequently this concentration decreases again.
  • the model shown in the lower right pane of Fig. 30 shows that at each sweat burst the lactate concentration increases, and during the subsequent rest period the lactate concentration only slowly decreases due to back diffusion into the tissue. At each subsequent sweat burst, the lactate concentration increases further, and finally after a number of sweat bursts a final maximum is reached and the sweat gland becomes inactive for a longer time, in spite of further nerve stimulation.
  • the system 300 may include a further sensor 166 (not visible in Fig. 31 ) downstream of the sensor 166 shown in Fig. 31 .
  • the sweat rate and biomarker sensors may, for instance, be provided at different locations to each other along the migratory path of the sweat droplets 112.
  • the electrowetting tiles 124 labelled 17 to 24 may transport the sweat droplets 112 to such an additional downstream sensor and/or to a waste container.
  • the migration velocity of the sweat droplets may be slowed down via the electrical connection scheme described above in relation to Fig. 28 .
  • the electrowetting tiles 124 labelled I to IV are activated, in between electrowetting waves passing along the electrowetting tiles labelled 1 to 24, thereby causing a droplet of a calibration fluid to be transported to the electrowetting tile 124 labelled 13.
  • the calibration fluid droplet may be subsequently migrated to the sensor 166, e.g. to a biomarker sensor, via the subsequent electrowetting wave passing along the electrowetting tiles labelled 1 to 24.
  • the known biomarker concentration in the calibration fluid droplet may then be measured, and, if required, a correction to the measured biomarker concentrations in the sweat droplets 112 may be correspondingly applied.
  • the apparatus, systems and methods of the present disclosure may be applied for non-invasive, semi-continuous and prolonged monitoring of biomarkers that indicate health and well-being, for example for monitoring dehydration, stress, sleep, children's health and in perioperative monitoring.
  • the present apparatus, systems and methods may be specifically applied to provide an early warning for sudden deterioration of patients in the General Ward and Intensive Care Unit, or for investigation of sleep disorders.
  • measurements may only be made in a spot-check fashion when a patient is visiting a doctor, although it is noted that the present disclosure may also be usefully applied in performing such spot-check measurements.

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EP19202953.6A EP3808270A1 (fr) 2019-10-14 2019-10-14 Appareil, système et procédé de surveillance d'écoulement de sueur
JP2022522387A JP7209129B2 (ja) 2019-10-14 2020-10-08 汗の流れを監視するための装置、システム及び方法
CN202080072261.8A CN114585306A (zh) 2019-10-14 2020-10-08 用于汗液流监测的装置、系统和方法
US17/769,024 US20240099647A1 (en) 2019-10-14 2020-10-08 Apparatus, system, and method for sweat flow monitoring
EP20786576.7A EP4044922B1 (fr) 2019-10-14 2020-10-08 Appareil, système et procédé de surveillance d'écoulement de sueur
PCT/EP2020/078304 WO2021074010A1 (fr) 2019-10-14 2020-10-08 Appareil, système et procédé pour la surveillance de l'écoulement de sueur

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CN113640357B (zh) * 2021-09-01 2024-04-12 中国科学院苏州纳米技术与纳米仿生研究所 一种实时连续检测电解质浓度的可穿戴汗液传感器装置
EP4159122A1 (fr) 2021-10-04 2023-04-05 Koninklijke Philips N.V. Appareil de transport de gouttelettes de sueur
WO2023073797A1 (fr) * 2021-10-26 2023-05-04 日本電信電話株式会社 Dispositif et procédé d'analyse de la transpiration
CN114680945A (zh) * 2022-04-02 2022-07-01 苏州大学 可穿戴式汗液自驱动主动收集、排出设备
EP4374963A1 (fr) 2022-11-23 2024-05-29 Koninklijke Philips N.V. Appareil d'électromouillage et son procédé de fonctionnement

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